Although now almost two decades of advances in the development and refinement of antiretroviral therapy have substantially diminished HIV-associated illness and mortality, the chronic management of HIV-infected patients remains complex. Both the acute and long-term toxicities of an expanding armamentarium of antiretroviral medications are becoming better understood and continue to complicate the successful management of this infection. Alternative treatment strategies are still clearly desirable, both for patients with access to ART and, on a worldwide basis, for the much greater number of patients with limited access to these expensive therapies. Our clinical research continues to address several important aspects of the following questions: how to optimally use and administer multi-class combination anti-retroviral therapy; how to integrate immune based therapies within a framework of ongoing antiretroviral therapy; how to develop a successful antiretroviral strategy that permits safe, periodic interruption of treatment in order to spare drug and/or reduce toxicities, and how to optimize the potential use of immune-based therapies as a means of decreasing exposure to antiretroviral drugs. A major highlight of this project has been to characterize the immunologic abnormalities associated with HIV infection, develop safe, practical immunologic approaches to the adjunctive therapy of patients with HIV infection, and utilize these immune based therapies as tools for obtaining valuable insights into the pathophysiologic mechanisms present in patients with HIV infection. One of the specific tools employed in this endeavor has been the use of subcutaneous administration of interleukin-2 (scIL-2) to reverse the CD4+ T cell decline associated with progressive HIV-1 infection. A series of randomized phase I-II studies were carried out that established this as a feasible method for increasing the CD4 count in patients with HIV infection; these studies were then extended to optimize the dosing regimens for maximal immunologic and virologic benefit while minimizing side effects. Intensive efforts are underway to better characterize the function, replication, and survival of lymphocytes following both acute and chronic stimulation by IL-2 therapy. Cohorts of patients are being followed who have received IL-2 treatment for periods that now extend to almost 16 years. A major finding of these studies, elucidated using two independent means of both in vivo and ex vivo lymphocyte labeling, has been the discovery that intermittent IL-2 therapy induces a marked prolongation of the survival of CD4+ T cell subsets, particularly both naive and central memory cell subsets. Extensive phenotypic study of these CD4+/CD25+ cytokine-expanded cells (CEN) shows them to express a unique pattern of surface markers distinguishable from other CD25+ populations such as T regulatory lymphocytes. The laboratory remains engaged in an extensive series of collaborations with a large number of extramural colleagues, both in the US and abroad, in the context of two major randomized phase III international clinical endpoint trials of sc IL-2. The goal of these studies is to determine whether the favorable effects of IL-2 therapy on CD4+ T cell number translate into a significant delay in the onset of AIDS-defining conditions and/or death in such patients versus the recipients of antiretroviral therapy alone. We have also served as lead center in a multi-center exploration of the safety and potential immunologic efficacy of an interleukin-2 analogue that has a selectively enhanced binding affinity for the high-affinity IL-2 receptor and a more favorable toxicity profile in preclinical studies. Interleukin-2 (IL-2) is also being studied for its potential role in supplementing ART therapy, specifically to determine whether it can be used as a ART-sparing regimen for those who experience an initial CD4+ T cell increase from its use. We have conducted a randomized, controlled trial of scIL-2 with and without ART interruption in an IL-2-experienced cohort to determine how successful IL-2 therapy may be in eliminating the need for continuous ART with sacrificing CD4+ cell numbers. We are also actively engaged in the design and implementation of similar exploratory studies of ART-sparing strategies with extramural collaborators to address different facets of this issue. In particular, we are the lead center in a randomized, controlled multi-center international trial recently launched to compare the effects of intermittent scIL-2 therapy with or without the use of peri-cycle antiretroviral treatment. We have also performed phase I/II work to determine the safety and preliminary antiviral efficacy of a novel CCR5 inhibitor compound. We have also recently engaged in a series of novel phase I/II research efforts to characterize both conventional and investigational antiviral agents of potential utility in the treatment of both seasonal influenza as well as avian (H5N1) influenza. We also continue our efforts to improve access to clinical trials by local minority populations through an outreach that includes a close relationship with local clinics for medically under-served populations. Finally, we continue an active role in helping establish a clinical research infrastructure in the South African National Defense Force military health-care system through our ongoing participation in the HIV research projects organized under Project Phidisa.